The present invention relates to certain compounds, pharmaceutical compositions containing the compounds, and the microbial production of the compounds. The compounds are useful as HIV integrase inhibitors.
References are made throughout this application to various published documents in order to more fully describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference in their entireties.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3"" termini of the linear proviral DNA; covalent joining of the recessed 3"" OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame (Ratner et al., Nature 1985, 313: 277). Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease (Toh et al., EMBO J. 1985, 4: 1267; Power et al., Science 1986, 231: 1567; Pearl et al., Nature 1987 329: 351). All three enzymes have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The applicants additionally demonstrate that inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro and integrase as a component of the preintegration complex in HIV infected cells. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication. The compounds of the present invention inhibit integrases of closely related lentiviruses such as HIV 2 and SIV, but not integrases from more distantly related retroviruses, for example RSV. These compounds do not inhibit binding or catalysis of other nucleic acid binding proteins, including enzymatic reactions such as those catalyzed by HIV reverse transcriptase, HIV Rnase H, Influenza transcriptase, Hepatitis C polymerase, Yeast DNA polymerase, DNase I, Eco RI endonuclease, or mammalian polymerase II.
Zhao et al. (J. Med Chem. 1997, 40: 937-941 and 1186-1194) describe hydrazide and arylamide HIV integrase inhibitors. Bis-catechols useful for inhibiting HIV integrase are described in LaFemina et al. (Antimicrobial Agents and Chemotherapy February 1995, 39:, 320-324).
Applicants have discovered that certain novel compounds are potent inhibitors of HIV integrase. These compounds are useful for the treatment of AIDS or HIV infections. More particularly, the present invention includes compounds of formula (I): 
wherein
R1 is xe2x80x94OH, xe2x80x94OCH3, or 
wherein Zxe2x88x92 is a counterion; each of R2, R3, and R4 is independently xe2x80x94OH or xe2x80x94OC(O)CH3; and R5 is (i) xe2x80x94OH when R1 is xe2x80x94OH or xe2x80x94OCH3 or (ii) xe2x80x94OC(O)CH3 when R1 is 
or a pharmaceutically acceptable salt thereof.
wherein
R1 is xe2x80x94OH, xe2x80x94OCH3, or 
wherein Zxe2x88x92 is a counterion; and each of R2, R3, and R4 is independently xe2x80x94OH or xe2x80x94OC(O)CH3; or a pharmaceutically acceptable salt thereof.
The present invention also includes use of these compounds in the inhibition of HIV integrase, the prevention of infection by HIV, the treatment of infection by HIV, and the treatment of AIDS and/or ARC, wherein the compounds are used per se or as their pharmaceutically acceptable salts or hydrates (when appropriate), either alone or as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. The present invention further includes the culture Actinoplanes sp. MA7220 (ATCC 202188) and processes for making compounds of the present invention employing the culture.
These and other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples, and appended claims.